Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices

ABSTRACT

Disclosed is a therapy for treating and for preventing periprosthetic bone loss by the administration of a bisphosphonate bone resorption inhibitor, e.g., alendronate, in patients who have an orthopedic implant device.

FIELD OF THE INVENTION

The instant invention relates generally to the use of alendronate toprevent periprosthetic bone loss in patients having an orthopedicimplant device.

Background of the Invention

A major problem with patients who have orthopedic implant devices orjoint prosthesis, such as hip replacements, is that many of these beginto fail after five years or so from the time that they are inserted. Thefailure rate increases exponentially with time so that many patientswith an aging hip prosthesis (10 to 15 years), experience pain at thesite of the implant and eventually require revision to the originalprocedure. Although initially this was considered to be a result offragmentation of the cement substances utilized in older hip prostheses,the problem continues to be observed even in the newer devices which donot rely on the use of cement. A hallmark of these patients is that atthe time they develop pain and loosening of the joint they have markedlyincreased bone turnover, especially bone resorption, in the boneimmediately adjacent to the implant. Evidence for this bone turnover canbe seen from the fact that bone scanning agents, which arebisphosphonates tagged with technetium, are often taken up at very highconcentrations in these areas indicating that there may well besignificant targeting of bisphosphonates to the periprosthetic bone.

There is a need in the art for localized controlled/extended releasedosage forms of bone growth promotant since in the United States, thereare approximately 5 million fractures and 265,000 prosthetic implantsper year. Of this population, there is about a 20-30% failure ratewithin five years of the operation, requiring a repeat surgery anddevice implant.

Normal bones are living tissues which undergo constant resorption andnew bone formation, with the net effect of maintenance of a constantmineral balance. The dual process is commonly called "bone turnover". Innormal growing bones, the mineral deposition exceeds the mineralresorption, whereas in certain pathological conditions, bone resorptionexceeds bone deposition, for instance due to malignancy or primaryhyperpamthyroidism, or in osteoporosis. In other pathological conditionsthe deposition of new bone may take place in undesirable amounts andareas leading to e.g. heterotopic ossification, osteosclerosis, andPaget's disease which is a combination of an abnormal high boneresorption followed by an abnormal calcium deposition. With orthopedicimplants, bone resorption may occur at an accelerated rate in theperiprosthetic area leading to net bone loss.

Most of the currently available therapeutic agents for the treatment ofosteoporosis, e.g. estrogens, act by reducing bone resorption in theosteoporotic patient. See the review article, "British Medical Bulletin"46 (1), p. 94-112 (1990).

Bisphosphonates are also known in the art as bone resorption inhibitors.

Alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidmonosodium trihydrate is a known bone resorption inhibitor and isdescribed in U.S. Pat. Nos. 4,922,007 and 5,019,651 (Merck).

Clodronate, (dichloromethylene)bisphosphonic acid disodium salt (Proctorand Gamble, is described in Belgium Patent 672,205 (1966) and itspreparation is found in J. Org. Chem 32, 4111 (1967).

Tiludronate, ([(4-chlorophenyl)thiomethylene]-bisphosphonic acid)(Sanofi) is described in U.S. Pat. No. 4,876,248 issued Oct. 24, 1989.

YM 175 ([(cycloheptylamino)methylene]bisphosphonic acid, disodium salt)by Yamanouchi is described in U.S. Pat. No. 4,970,335 issued Nov. 13,1990.

BM 21.0995 (1-Hydroxy-3-(methylpentylamino)-propylidene-bisphosphonate)by Boehringer-Mannheim--is described in U.S. Pat. No. 4,927,814 issuedMay 22, 1990.

A study by Proctor and Gamble (Norwich Eaton Pharmaceuticals) usingrisedronate, whose chemical name is sodium trihydrogen[1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, in combination withestrogen showed a positive effect on bone loss in ovariectomized rats(published in Abstracts 731 and 732 at the Fall 1992 ASBMR meeting inMinnesota).

The article, "J. Clin. Invest.", Jan. 1992, 89 (1), p. 74-78 by J. Chowet al., describes the effect of estrogen on ovariectomized rats in whichbone resorption was suppressed by pamidronate whose chemical name is3-amino-1-hydroxy propylidene-bisphosphonic acid disodium salt. Theyconcluded that estrogen inhibits bone resorption and also stimulatesbone formation.

Another Proctor and Gamble compound, piridronate,[2-(2-pyridinyl)ethylidene]-bisphosphonic acid, monosodium salt isdescribed in U.S. Pat. No. 4,761,406 as having bone resorptioninhibition activity.

The article, "Monatschefte" 99, 2016 (1968) by F. Kasparet describes thesynthesis of etidronate, (1-hydroxyethylidene)-bisphosphonic acid,disodium salt, (Proctor and Gamble).

However, the above cited art does not suggest or describe the use of abisphosphonate in situations to specifically prevent bone resorption inthe periprosthetic bone area of an orthopedic implant device.

What is desired in the art is a therapy to optimally treat the boneresorption in the periprosthetic area of an implant device i.e., thebone area which is in contact and close proximity to the device implant,to retard the loosening of the device and to alleviate the painassociated with this condition.

SUMMARY OF THE INVENTION

We have discovered that a bisphosphonate can be used in such patientsfor the prophylaxis and treatment of failure of joint prostheses, e.g.for the hip or knee. Long term administration of a relatively low doseof a bisphosphonate, e.g., alendronate, can prevent the periprostheticbone resorption process and thereby maintain the integrity of the totalstructure.

The treatment can be further extended to patients with symptomaticfailure of a joint prostheses or internal fixation device.Bisphosphonates, e.g., alendronate, are able to reverse the loosening ofa prosthesis once it has occurred, and there is also some alleviation ofthe bone pain which accompanies this complication of joint replacement.

By this invention there is provided a method for treating and/orpreventing (reducing the risk of) periprosthetic bone loss in a subjecthaving an orthopedic implant device comprising administering to saidsubject a pharmaceutically effective dose of a bisphosphonate. Thebisphosphonate applicable in the method includes: alendronate,clodronate, tiludronate, YM 175, BM 21.0995, etidronate, risedronate,piridronate, pamidronate, or combinations thereof.

BRIEF DESCRIPTION OF THE FIGURE

The FIGURE illustrates the effects of alendronate on bone resorption atdifferent concentrations, on the rat bone marrow ablation model in whichbone is regenerated in the voided regions of the bone.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The bisphosphonates described above are useful in the invention process.Preferred are residronate, clodronate, tiludronate and alendronate andparticularly preferred is alendronate.

The method disclosed herein can be used to treat human subjects who havea prosthesis, i.e., a medical implant device.

The method involves the administration of a bisphosphonate in anosteogenically effective amount to inhibit bone resorption in theperiprosthetic bone area of a medical implant device.

By the term "periprosthetic bone area" as used herein is meant the areaof bone which is an contact with the medical implant device or in theimmediate proximity thereof.

The term "inhibition of bone resorption" as used herein refers toprevention of bone loss, especially the inhibition of removal ofexisting bone either from the mineral phase and/or the organic matrixphase, through direct or indirect alteration of osteoclast formation oractivity. Thus, the term "inhibitor of bone resorption" as used hereinrefers to agents that prevent bone loss by the direct or indirectalteration of osteoclast formation or activity.

The term "osteogenically effective" as used herein means that amountwhich decreases the turnover of mature bone. As used herein, anosteogenically effective dose is also "pharmaceutically effective."

The term "subject" as used herein refers to a living vertebrate animalsuch as a mammal in need of treatment, i.e., in need of periprostheticbone repair. The periprosthetic bone loss may arise in cases of systemicbone disease, as in osteoporosis (of any etiology), osteoarthritis,Paget's disease, osteomalacia, multiple myeloma and other forms ofcancer.

The term "treatment" or "treating" as used herein shall mean (1)providing a subject with an amount of a bisphosphonate sufficient to actprophylactically on periprosthetic bone to prevent the development of aweakened and/or unhealthy state; and/or (2) providing a subject with asufficient amount of a bisphosphonate so as to alleviate or eliminate adisease state and/or the symptoms of a disease state in the area ofperiprosthetic bone.

The methods of the invention are useful for treating defects anddisorders in the periprosthetic area of bone which result in a weakenedstructure and/or pain.

In accordance with one method of use, the bisphosphonate may beadministered to the periprosthetic bone area systemically either orallyand/or parenterally, including subcutaneous or intravenous injection.Additionally, the bisphosphonate may be delivered in a slow release formfrom a suitable carrier.

In accordance with another method of use, the bisphosphonate may beadministered locally to the specific periprosthetic area in need of bonegrowth or repair. Thus, the bisphosphonate may be implanted directly atthe site to be treated, for example, by injection or surgicalimplantation in a sustained-release carrier. Suitable carriers includehydrogels, controlled- or sustained-release devices (e.g., an Alzet®minipump), polylactic acid, and collagen matrices. Presently preferredcarriers are formulations of atelopeptide collagen containingparticulate calcium phosphate mineral components, such combinations ofhomologous or xenographic fibrillar atelopeptide collagen (for exampleZyderm® Collagen Implant, available from Collagen Corporation, PaloAlto, Calif.) with hydroxapatitetricalcium phosphate (HA-TCP, availablefrom Zimmer, Inc., Warsaw, In.). It is presently preferred to administerimplant compositions containing alendronate in a collagen/mineralmixture implant.

Bisphosphonate delivered in sustained-release vehicles is useful forimproving implant fixation, for example, for improving in growth of newbone into a metal prosthesis in joint reconstruction or orthopedicimplants.

Alternatively, orthopedic implants can be coated with bisphosphonate toenhance attachment of the implant device to the bone at the time of theimplant operation.

In general, implant devices may be coated with a bisphosphonate asfollows. The bisphosphonate is dissolved at a concentration in the rangeof 0.01 μg/ml to 200 mg/ml in phosphate-buffered saline (PBS) containing2 mg/ml serum albumin. The porous end of an implant is dipped in thesolution and is airdried (or lyophilized) or implanted immediately intothe bony site. The viscosity of the coating solution is increased, ifdesired, by adding hyaluronate at a final concentration of 0.1 mg/ml to100 mg/ml or by adding other pharmaceutically acceptable excipients.Alternatively, the solution containing the bisphosphonate, is mixed withcollagen gel or human collagen (e.g. Zyderm® Collagen Implant, CollagenCorp., Palo Alto, Calif.) to a final collagen concentration of 2 mg/mlto 100 mg/ml to form a paste or gel, which is then used to coat theporous end of the implant device. The coated implant device is placedinto the periprosthetic bony site immediately or is airdried andrehydrated with PBS prior to implanting, with the objective ofmaximizing new bone formation into and around the implant whileminimizing the ingrowth of soft tissue into and around the implant site.

Pharmaceutical formulations of the invention which include abisphosphonate inhibitor of bone resorption for administration willgenerally include an osteogenically effective amount of thebisphosphonate to promote bone growth, in addition to a pharmaceuticallyacceptable excipient. Suitable excipients include most carriers approvedfor parenteral administration, including water, saline, Ringer'ssolution, Hank's solution, and solutions of glucose, lactose, dextrose,ethanol, glycerol, albumin, and the like. These compositions mayoptionally include stabilizers, antioxidants, antimicrobials,preservatives, buffering agents, surfactants, and other accessoryadditives. The bisphosphonate inhibitor of bone resorption may also bedelivered in a sustained release form from a suitable carrier.

A presently preferred vehicle comprises phosphate-buffered saline (PBS)or isotonic citrate buffer. A thorough discussion of suitable vehiclesfor parenteral administration may be found in E. W. Martin. "Remington'sPharmaceutical Sciences" (Mack Pub. Co., current edition sectionsrelating to the excipient vehicles and formulating being incorporatedherein by reference to disclose such). Such formulations are generallyknown to those skilled in the art and are administered systemically toprovide systemic treatment.

The precise dosage of bisphosphonate necessary will vary with the age,size, sex and condition of the subject, the nature and severity of thedisorder to be treated, and the like; thus, a precise effective amountcannot be specified in advance and will be determined by the caregiver.However, appropriate amounts may be determined by routineexperimentation with animal models, as described below. In generalterms, an effective dose for biphosphonate is about 1.5 to 3000 μg/kgper day of body weight and preferably about 10 μg/kg to about 200 μg/kgper day of body weight. A particularly preferred dosage is 10 mg per dayper person.

Effective doses for local administration will be about 0.001 μg to 1 mgper application site.

The pharmaceutical compositions according to the present inventioncontaining bisphosphonate may be prepared for use in the form ofcapsules or tablets or in solution for oral administration or forsystemic use. The compositions are advantageously prepared together withinert carriers such as sugars (saccharose, glucose, lactose), starch andderivatives, cellulose and derivatives, gums, fatty acids and theirsalts, polyalcohols, talc, aromatic esters.

Some typical pharmaceutical formulations containing alendronate,4-amino-1-hydroxybutane-1,1-diphosphonic acid monosodium salttrihydrate, are shown here below:

    ______________________________________                                        ALENDRONATE TABLETS (WHITE), 200 MG                                           ______________________________________                                                     COMPOSITION IN MG/TABLET                                         INGREDIENT     2.5 mg* 5.0 mg* 10.0 mg*                                                                             40.0 mg*                                ______________________________________                                        Alendronate    3.26    6.55    13.05  51.21                                   Lactose NF Anydrous                                                                          113.74  110.45  103.95 64.79                                   Microcrystalline Cellulose NF                                                                80.0    80.0    80.0   80.0                                    Magnesium Stearate                                                                           1.00    1.00    1.00   1.00                                    Impalpable NF                                                                 Croscarmellos Sodium NF                                                                      2.00    2.00    2.00   2.00                                    Type A                                                                        ______________________________________                                         *Taken as the anhydrous monosodium saltactive ingredient.                    OPERCOLATED CAPSULES                                                                                 1             2                                        ______________________________________                                        Alendronate            mg 6.5        mg 2.5                                   Lactose                110.0         110.0                                    Avucek Ph101           80.0          80.0                                     Aldisol/NF Type A      2.0           2.0                                      Magnesium Stearate     1.0           1.0                                                     Total   202.5   Total 197.5                                                   Weight          Weight                                         ______________________________________                                        EFFERVESCENT                                                                  GRANULATES                                                                    ______________________________________                                        Alendronate             mg 5.0                                                Anhydrous Sodium Carbonate                                                                            12.0                                                  Sodium Bicarbonate      63.0                                                  Anhydrous Citric Acid   110.0                                                 Sodium Saccharinate     5.0                                                   Saccharose              493.0                                                 Dehydrated Lemon Juice  55.0                                                  Natural Essence of Lemon                                                                              2.0                                                   Total Weight            748                                                   ______________________________________                                        FORMULATIONS                                                                  SUITABLE FOR INJECTION                                                        ______________________________________                                        Alendronate      mg    0.5    mg      1.00                                    Sodium Hydroxide       0.25           0.25                                    Sodium Chloride        8.40          16.30                                    Purified Water q h                                                                             ml    1.0    ml     12.0                                     ______________________________________                                    

Bisphosphonate drugs which prevent bone loss and/or add back lost bonecan be evaluated in the ovariectomized rat. This animal model is wellestablished in the art (see, for example, Wronski, et al. (1985)"Calcif. Tissue Int." 37:324-328; Kimmel, et al. (1990) "Calcif. TissueInt." 46:101-110; and Durbridge, et al. (1990) "Calcif. Tissue Int."47:383-387; these references are hereby incorporated in their entirety).Wronski, et al. ((1985) "Calcif. Tissue Int." 43:179-183)) describe theassociation of bone loss and bone turnover in the ovariectomized rat.Bisphosphonate drugs applicable in the instant invention are active inthis assay.

EXAMPLE Alendronate Effects on Bone Formation and Resorbability of BoneFormed During Alendronate Treatment

To study the effects of alendronate during rapid bone formation, amodified bone marrow ablation model in the rat described in J. BoneMiner. Res. Vol. 8, pp. 379-388 (1993) by L. J. Suva et al., was used.In the rat, extraction of bone marrow (ablation) from a long boneresults in rapid bone formation which fills 25% of the marrow cavitywith cancellous bone (Cn) within 6 to 7 days. This bone is then fullyresorbed (replaced) within the next 15 days. When rats were orallytreated with 1, 2, 8 or 40 μg/kg alendronate day s.c. for 6 days,post-ablation, there was no difference in bone volume at 7 days (See theFIGURE), indicating that alendronate has no detectable effect on boneformation. In the FIGURE, Cn-BV/TV% represents cancellous bone volumedivided by total structure volume; SEM represents standard error of themean; ALN is alendronate; Fisher PLSD is a standard statistical leastsquares technique. After treatment was stopped, the amount of boneremaining in the marrow cavity at the various doses was examined at 4,14, 24 and 54 days later. For an alendronate dose of 1 μg/kg, bone wascompletely resorbed at 14 days, no different from controls. At 2μg/kg/day, bone was also completely resorbed 24 days after cessation oftreatment. At 8 and 40 μg/kg/day, bone was also resorbed, albeit moreslowly, resulting in a retention of about 33% and 50%, respectively, at54 days (See the FIGURE). These findings show that, at levels muchhigher than a human dose, there is no interference at all with boneformation in this model, and that bone formed at these doses is fullyresorbable, albeit more slowly than occurs with lower doses.

This data is consistent with the method of administering abisphosphonate, e.g., alendronate, to a patient's periprosthetic bonearea to prevent bone resorption and a weakening at the site of themedical implant device. The slowing of the rate of bone resorption, butnot its complete inhibition, is predicted to be associated with animprovement in the local bone balance in the periprosthetic bone whichwould provide greater integrity to the overall bone and prosthesisstructure.

What is claimed is:
 1. A method of preventing loosening of an orthopedicprosthesis in a patient comprising administering orally to the patient abone resorption inhibiting amount of alendronate or a pharmaceuticallyacceptable salt thereof.
 2. A method according to claim 1 wherein thepharmaceutically acceptable salt is alendronate monosodium trihydrate.3. A method of preventing loosening of a hip prosthesis in a patientcomprising orally administering to the patient 6.55 mg or 13.05 mgalendronate monosodium trihydrate daily.
 4. A method of preventing painassociated with loosening of an orthopedic prosthesis in a patientcomprising administering to the patient a bone resorption inhibitingamount of alendronate or a pharmaceutically acceptable salt thereof. 5.A method according to claim 4 wherein the pharmaceutically acceptablesalt is alendronate monosodium trihydrate.
 6. A method of preventingpain associated with the loosening of a hip prosthesis in a patientcomprising orally administering to the patient 6.55 mg or 13.05 mgalendronate monosodium trihydrate daily.